α-Melanocyte stimulation hormone (α-MSH) is a hormone derived from pro-opiomelanocortin (POMC) (Nonpatent Document 1), and referred to as a melanocortin peptide along with β-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH). α-MSH is known to exhibit an inhibitory action on the production of inflammation- or fibrosis related mediators associated with various pathogenesis, and exhibit efficacies in autoimmune disease models such as colitis, uveoretinitis, and arthritis (Nonpatent Document 2). Also, α-MSH analogs have been developed for use in the treatment of protoporphyria, acute renal failure, or postoperative pain.
Melanocortin receptors (MCRs), which are receptors for α-MSH, are seven-transmembrane G-protein-coupled receptors (GPCRs), and the activation thereof increases the intracellular cyclic AMP (cAMP) (Nonpatent Document 3). There are five subtypes of MCRs, i.e., MC1R to MC5R.
MC1R is a receptor which is mainly activated by α-MSH, and expressed in melanocytes, immune and inflammatory cells, fibroblasts, keratinocytes, endothelial cells, glial cells, and the like. Thus, the activation of MC1R is known to increase the cAMP level in MC1R-expressing cells, and produce effects such as melanogenesis in a skin and homeostasis against external stimuli (Nonpatent Document 4), anti-inflammatory effects, and inhibitory effects on tissue fibrosis (Nonpatent Document 5). MC2R is a receptor which poorly responds to α-MSH and activated mainly by ACTH, and highly expressed in adrenal cortex. The activation of MC2R is known to produce steroidogenesis effects. MC3R is a receptor which is activated mainly by γ-MSH and ACTH, and expressed in central nerves, macrophage, and the like. The activation of MC3R is known to produce effects such as regulation of autonomic function and anti-inflammatory effects. MC4R is a receptor which is activated mainly by α-MSH and ACTH, and expressed in central nerves and the like. Thus, the activation of MC4R is known to produce effects such as feeding suppression and enhancement of erectile function. MC5R is a receptor activated mainly by α-MSH, and expressed in exocrine glands, lymphocytes, and the like. The activation of MC5R is known to produce effects such as exocrine fluid regulation and immune function regulation. Thus, the activation of these melanocortin receptors (MCRs) is expected to produce effects such as immune regulation, anti-inflammation, and suppression of tissue fibrosis through the formation of cAMP.
Meanwhile, documents such as Patent Document 1 and Patent Document 2 are known to disclose a pyrrolidine compound having a carbamoyl group at the position 3 of pyrrolidine. The compound disclosed in Patent Document 1 also has an alkyl group, an aryl group, or a heteroaryl group as a substituent at the position 2 of pyrrolidine and binds to HDM2 to exhibit anticancer effects. However, Patent Document 1 does not disclose a pyrrolidine compound having substituents at the position 1, position 3, and position 4 like the compound of the present invention.
Also, the compound disclosed in Patent Document 2 is a compound wherein the carbamoyl group at the position 3 of pyrrolidine is substituted with a pyrrolidinyl group. However, Patent Document 2 does not disclose a compound wherein the carbamoyl group at the position 3 of pyrrolidine is substituted with an imidazolyl group like the compound of the present invention.